Eprosartan loaded mesoporous silica nanoparticles embedded in mucoadhesive buccal films: A strategy for improved bioavailability

Abstract

Eprosartan is a selective angiotensin receptor blocker used to treat essential hypertension. However, it has a low oral bioavailability of only 13 % as it is categorized as BCS class II and undergoes first-pass metabolism. Therefore, incorporating eprosartan into mesoporous silica nanoparticles (MSNs)-loaded buccal film might augment its bioavailability. The MSNs were formulated using the incipient wetness method, and an I-optimal design was utilized for optimization purposes. The independent variables were the drug-to-mesoporous silica ratio and the type of mesoporous silica. The entrapment efficiency percent (EE %), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and percentage of drug released after 6 h (Q6 %) were assessed. The optimized MSNs formula was assessed by evaluating its morphology, Fourier-transform infrared spectroscopy (FTIR), and thermal analysis. Then, the optimized MSNs formula was embedded into a mucoadhesive buccal film, which was characterized via ex vivo permeation and pharmacokinetics studies. The optimized MSNs formula was spherical and had EE % of 99.50 ± 0.54 %, PS of 197.9 ± 2.2 nm, PDI of 0.442 ± 0.008, ZP of −16.21 ± 0.87 mV, and Q6 % of 93.00 ± 1.9 %. The FTIR ensured the drug’s uptake by the porous structure, while thermal analysis confirmed its amorphous state after loading into MSNs. The MSNs-loaded buccal film augmented the apparent permeability coefficient by 4.88 folds compared to free-drug film. The C_max and AUC_0-t of MSNs-loaded buccal film were 2.88-fold and 2.63-fold, respectively, compared to the oral eprosartan, while the T_max was shortened to 0.5 h instead of 1 h. This study confirmed the capability of MSNs-loaded buccal film to enhance the bioavailability of eprosartan.

Introduction

Eprosartan is a non-biphenyl selective angiotensin receptor blocker usually prescribed for treating essential hypertension. With unique pharmacological characteristics, dual action mechanisms, and clinical effectiveness, eprosartan offers additional advantages over other angiotensin receptor blockers, such as telmisartan and losartan, especially in patients with coagulation-related abnormalities and peripheral resistance [1]. However, eprosartan possesses a low oral bioavailability of only 13 % in humans because of its poor aqueous solubility of 0.00866 mg/mL and extensive first-pass metabolism [2]. Furthermore, eprosatan is a substrate for P-gp, an efflux transporter, causing possible reduced therapeutic activity [3]. Consequently, a large dose of 800 mg is usually given for treating hypertension and various cardiac diseases, which frequently triggers adverse or side effects [4], since it has been retrieved that up to 90 % of active pharmaceutical ingredients in the pipeline and 40 % of medications in the market acquire low aqueous solubility based on the Biopharmaceutical Classification System (BCS) [5]. Several strategies have been developed throughout the past years to address this challenge. One of these strategies is the fabrication of nanocarrier-based drug delivery systems. These systems have been designed as an applicable approach to deal with crucial challenges, such as poor drug solubility accompanying conventional drug delivery systems [6].

Moreover, nanocarriers enable enhanced interaction with the biological barriers due to their diminished dimensions, offer a huge surface area for improved functionality, enable alteration of their physical characteristics, and allow the elaboration of advanced drug delivery systems with varied features [7]. Nanocarrier-based drug delivery systems loaded with poorly soluble antihypertensive drugs help achieve better drug concentration, stability, pharmacokinetic and pharmacodynamic profiles. Also, it decreases the side effects accompanying the administration of a high dose of antihypertensive drugs [8]. Several studies have investigated the utilization of nanocarriers for enhancing the bioavailability of eprosartan, such as polymeric nanoparticles where polymeric nanoparticles of eprosartan were developed using Eudragit L-100 and S-100 as polymers by nan precipitation method. Eudragit L-100 formulations formed stable nanoparticles with 81.6 % entrapment efficiency (EE%) and better drug solubility and dissolution rate than Eudragit S-100-based formulations [9]. Also, eprosartan-loaded bilosomes were fabricated with EE% ranging from 60.61 ± 0.86 to 63.29 ± 0.81 %, and the in vivo pharmacodynamic study demonstrated that the eprosartan loaded bilosomes showed a nephro-protecting outcome [10]. Moreover, eprosartan nanopowder formula was prepared and yielded higher exposure (4600 ± 36 ng mL−1 h) than pure drug (2349 ± 34 ng mL−1 h) [11]. Finally, nano-transferosomes intended for transdermal delivery of eprosartan were developed, where a higher transdermal flux was achieved in these studies with EE% exceeding 90 % [[12], [13], [14]].

Nanocarriers are usually divided into two main classes: organic and inorganic. Inorganic nanocarriers offer numerous merits over organic nanoparticles in terms of stability. Mesoporous silica nanoparticles (MSNs) are an extensively utilized inorganic nanocarrier for a wide variety of drug delivery and imaging purposes. MSNs can be fabricated with numerous particle sizes, pore sizes, and morphologies, enabling several preferences for targeted drug delivery [15].
Moreover, MSNs possess exclusive and outstanding characteristics, such as biocompatibility, non-toxicity, and stable aqueous dispersion. In addition, the vast surface area and the high pore volume permit the loading of excessive quantities of active pharmaceutical ingredients [16]. Also, their flexibility is further increased by their ability to incorporate a diversity of therapeutic agents, including both hydrophilic and hydrophobic drugs [17,18].

Moreover, the surface of MSNs contains free hydroxyl (silanol) groups, which promote specific interactions with adsorbed molecules, such as hydrogen bonding. Also, the silanol groups can be functionalized to provoke superior management of both the drug encapsulation and release characteristics. MSNs bear additional and remarkable merit for the poorly soluble drugs as it has been found that the adsorbed medications in the porous structure of the MSNs materials exist in the amorphous phase, achieving augmented dissolution of a poorly soluble drug and rapid release compared to crystalline substances [[19], [20], [21]]. Therefore, MSNs can improve drug pharmacokinetic parameters and diminish side effects by delivering an accurate dosage of drugs to a precise site rather than the recurrent systemic delivery [22]. Consequently, MSNs are considered a practical approach for addressing the issues of poorly soluble drugs.

Among mesoporous silica (MPS) materials, the most widely investigated is SBA-15 silica (SBA = Santa Barbara Amorphous), typically owning a very consistent pore structure of unidirectional channels [23]. It also displays attractive characteristics, such as large specific surface areas, high thermal stability, uniform-sized pores (4–30 nm), high surface-to-volume ratio, thick framework walls, and desirable textural porosity [24]. SBA-15 offers distinct advantages for drug delivery in comparison to other MPS materials, such as MCM-41 and MCM-48. Its larger pore size (4–30 nm vs. 2–4 nm in MCM analogues) accommodates higher drug loading and smoother release kinetics, which is critical for a bulky molecule. Additionally, SBA-15’s thicker walls enhance hydrothermal stability, ensuring structural integrity during drug loading and release. The 2D hexagonal pores also simplify amino-functionalization compared to MCM-48’s 3D cubic structure, enabling better control over surface modifications [[25], [26], [27]].

The buccal route has been significantly investigated as a substitute for the oral route as a site for drug administration. The buccally absorbed drug bypasses first-pass metabolism to reach the systemic circulation, leading to enhanced bioavailability [28]. Several earlier research works have studied the utilization of buccal delivery to improve the bioavailability of antihypertensive medications and provide better therapeutic effects [[29], [30], [31]].

To our knowledge, there have been no previous studies so far regarding the incorporation of eprosartan into MSNs nor the fabrication of eprosartan-loaded delivery systems intended for buccal delivery to enhance its bioavailability. Therefore, in this study, the capability of eprosartan-loaded MSNs incorporated into a buccal film to improve the pharmacokinetics profile of eprosartan was investigated. Eprosartan-loaded MSNs formulae were fabricated and optimized utilizing an I-optimal design (Design-Expert software version 13 (Stat Ease, Inc., Minneapolis, MN, USA) where drug to MPS ratio and type of MPS material (SBA-15 or amino-functionalized SBA-15) were elected as independent variables. The selected MSNs formula was contained in a mucoadhesive film and further assessed regarding ex vivo permeation and mucoadhesion force. Finally, an in vivo pharmacokinetics assessment was accomplished to evaluate the pharmacokinetics parameters of eprosartan-loaded MSNs buccal film compared to oral administration of eprosartan.

Materials

Eprosartan was a gift from Hochster Pharmaceutical Industries (Badr, Cairo, Egypt). Spheroidal mesoporous silica SBA-15 and amino-functionalized mesoporous silica SBA-15 (PS below 100 nm) were purchased from Nanogate (Cairo, Egypt). Hydroxy propyl methyl cellulose K4M attained from Colorcon (Kent, UK). Carbopol P934 from Delta Pharma (Cairo, Egypt). Chitosan and propylene glycol were bought from El-Nasr Pharmaceutical Chemicals Co. (Cairo, Egypt). Sodium alginate and polyvinyl pyrrolidone.

Menna M. Abdellatif, Rana M. Gebreel, Eprosartan loaded mesoporous silica nanoparticles embedded in mucoadhesive buccal films: A strategy for improved bioavailability, Journal of Drug Delivery Science and Technology, Volume 112, 2025, 107248, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2025.107248.